Fumaric acid amides

ABSTRACT

The present invention relates to the use of fumaric acid amides of the general formula (I)  
                 
 
     wherein  
     R 1  represents OR 3  or a D- or L-amino acid radical —NH—CHR 4 —COOH bonded via an amide bond, wherein R 3  is hydrogen, a straight-chained or branched, optionally substituted C 1-24  alkyl radical, a phenyl radical or C 6-10  aralkyl radical and R 4  is a side chain of a natural or synthetic amino acid and  
     R 2  represents a D- or L-amino acid radical —NH—CHR 5 —COOH bonded via an amide bond or a peptide radical comprising 2 to 100 amino acids bonded via an amide bond, wherein R 5  is a side chain of a natural or synthetic amino acid,  
     for preparing a drug  
     (1) for the therapy of an autoimmune disease;  
     (2) for use in transplantation medicine;  
     (3) for the therapy of mitochondrial diseases  
     (4) for the therapy of NF-kappaB mediated diseases

[0001] The present invention relates to certain fumaric acid mono- anddiamides, or monoamido fumaric acid monoesters, respectively, as well asthe use of such compounds for preparing a drug and drugs containing saidcompounds.

[0002] For a long time, fumaric acid dialkyl esters as well as fumaricacid monoalkyl esters and salts thereof have been successfully used fortreating psoriasis. Said use is described in a number of patents, forexample EP-A-0 188 749, DE-95 30 327, DE 26 21 214 or EP-B-0 312 697.

[0003] The use of fumaric acid mono- or diesters is also described forthe treatment of autoimmune diseases such as polyarthritis, multiplesclerosis (cf. DE 197 21 099.6 and DE 198 53 487.6), but also for use intransplantation medicine (cf. DE 198 53 487.6 and DE 198 39 566.3). Theuse of fumaric acid mono- and diesters for the treatment of NF-kappaBmediated diseases and the treatment of mitochondrial diseases is alsoknown from the unpublished German applications DE 101 01 307.8 and DE100 00 577.2. However, all the cited documents merely describe fumaricacid mono- and diesters, optionally in the form of certain salts, i.e.compounds wherein one or both acid functions of the fumaric acid areesterified with an alcohol.

[0004] Because of their volatility and sublimability, however, theabove-mentioned fumaric acid esters have the disadvantage of beingdifficult to handle when preparing pharmaceutical products, especiallythose in solid form for oral administration. Specifically thepreparation of such products requires protective measures such as theuse of breathing masks, gloves, protective clothing.

[0005] In addition, the fumaric acid esters are absorbed in thegastro-intestinal tract after oral administration and taken upunspecifically from the bloodstream by all body cells. Therefore, it isnecessary to administer high dosages in order to provide atherapeutically effective level of the active ingredient on or in thetarget cells. Such high dosages in turn lead to the known side effectsof a fumaric acid therapy like flush symptoms (reddening) orgastrointestinal irritation (nausea, diarrhoea, winds). Even though suchside effects may be reduced considerably by administering the activeingredient in the form of micro-tablets as described in the above-citedprior art, they cannot be avoided altogether.

[0006] At the same time, the fumaric acid esters are rapidly hydrolysedin the blood and the products of said hydrolysis, alcohol and fumaricacid or fumaric acid monoester, metabolised. In order to maintaintherapeutically effective levels repeated and frequent administration istherefore necessary. Even though a certain adaptation is observedconcerning the side effects, a further reduction of the side effect ratewould be desirable.

[0007] Therefore, it is an object of the present invention to providefumaric acid derivatives, which may be administered strategically, aremore resistant to hydrolysis and easier to handle, and the use of suchderivatives.

[0008] The present object is achieved by certain fumaric acid mono- anddiamides or monoamido fumaric acid monoesters, respectively, the usethereof for preparing drugs for the therapy of certain diseases anddrugs containing the same.

[0009] Fumaric acid diamides and monoamides have also been described inU.S. Pat. No. 5,242,905 and U.S. Pat. No. 5,214,196 to Blank for thetreatment of psoriasis. However, these cited publications merelydescribe the preparation of single fumaric acid mono- or diamides, butnot the preparation of pharmaceutical products and the application ofthe amides on human beings. A theoretical advantage of the fumaricamides over the fumaric acid esters cited by the above publications isthe provision of certain amino acids from the fumaric amides in thekeratinocytes in order to complement metabolic deficiencies inpsoriasis.

[0010] Surprisingly, the inventors have now found that the fumaric acidmono- and diamides or monoamido fumaric acid monoesters may be usedadvantageously for the therapy of a variety of diseases. Specifically,the first aspect of the present invention therefore relates to the useof fumaric acid amides of the general formula (I)

[0011] wherein

[0012] R₁ represents OR₃ or a D- or L-amino acid radical —NH—CHR₄—COOHbonded via an amide bond, wherein R₃ is hydrogen, a straight-chained orbranched, optionally substituted C₁₋₂₄ alkyl radical, preferably a C₁₋₆alkyl radical, a phenyl radical or C₆₋₁₀ aralkyl radical and R₄ is aside chain of a natural or synthetic amino acid and R₂ represents a D-or L-amino acid radical —NH—CHR₅—COOH bonded via an amide bond or apeptide radical comprising 2 to 100, preferably 2 to 30 amino acidsbonded via an amide bond, wherein R₅ is a side chain of a natural orsynthetic amino acid,

[0013] for preparing a drug

[0014] (1) for the therapy of an autoimmune disease selected from thegroup consisting of polyarthritis, especially rheumatoid arthritis,multiple sclerosis, graft-versus-host reactions, juvenile-onsetdiabetes, Hashimoto's thyroiditis, Grave's disease, systemic Lupuserythematodes (SLE), Sjogren's syndrome, pernicious anaemia and chronicactive (=lupoid) hepatitis;

[0015] (2) for use in transplantation medicine(Host-versus-graft-reactions);

[0016] (3) for the therapy of mitochondrial diseases selected from thegroup consisting of Parkinson syndrome, Alzheimer's disease, ChoreaHuntington disease, retinopathia pigmentosa or forms of mitochondrialencephalomyopathy; as well as

[0017] (4) for the therapy of NF-kappaB mediated diseases selected fromthe group consisting of progressive systemic sclerodermia,osteochondritis syphilitica (Wegener's disease), cutis marmorata (livedoreticularis), Behcet disease, panarteriitis, colitis ulcerosa,vasculitis, osteoarthritis, gout, artenosclerosis, Reiter's disease,pulmonary granulomatosis, types of encephalitis, endotoxic shock(septic-toxic shock), sepsis, pneumonia, encephalomyelitis, anorexianervosa, hepatitis (acute hepatitis, chronic hepatitis, toxic hepatitis,alcohol-induced hepatitis, viral hepatitis, jaundice, liverinsufficiency and cytomegaloviral hepatitis), Rennert T-lymphomatosis,mesangial nephritis, post-angioplastic restenosis, reperfusion syndrome,cytomegaloviral retinopathy, adenoviral diseases such as adenoviralcolds, adenoviral pharyngoconjunctival fever and adenoviral ophthalmia,AIDS, Guillain-Barré syndrome, post-herpetic or post-zoster neuralgia,inflammatory demyelinising polyneuropathy, mononeuropathia multiplex,mucoviscidosis, Bechterew's disease, Barett oesophagus, EBV(Epstein-Barr virus) infection, cardiac remodeling, interstitialcystitis, diabetes mellitus type II, human tumour radiosensitisation,multi-resistance of malignant cells to chemotherapeutic agents(multidrug resistance in chemotherapy), granuloma annulare and cancerssuch as mamma carcinoma, colon carcinoma, melanoma, primary liver cellcarcinoma, adenocarcinoma, kaposi's sarcoma, prostate carcinoma,leukaemia such as acute myeloid leukaemia, multiple myeloma(plasmocytoma), Burkitt lymphoma and Castleman tumour.

[0018] In a second aspect, the present invention relates to fumaric acidamides of the formula (I)

[0019] wherein

[0020] R₁ represents OR₃ or a D- or L-amino acid radical —NH—CHR₄—COOHbonded via an amide bond, wherein R₃ is hydrogen, a straight-chained orbranched, optionally substituted C₁₋₂₄ alkyl radical, preferably a C₁₋₆alkyl radical, a phenyl radical or C₆₋₁₀ aralkyl radical and R₄ is aside chain of a natural or synthetic amino acid and

[0021] R₂ represents a D- or L-amino acid radical —NH—CHR₅—COOH bondedvia an amide bond or a peptide radical comprising 2 to 100 amino acids,preferably 2 to 30 amino acids, bonded via an amide bond, wherein R₅ isa side chain of a natural or synthetic amino acid,

[0022] with the proviso that

[0023] when R₃═H, R₂ is a peptide radical selected from the groupconsisting of peptide hormones, growth factors, cytokines,neurotransmitters, neuropeptides, antibody fragments, coagulationfactors and cyclosporines as well as derivatives and fragments thereof;and

[0024] when R₁═NH—CHR₄—COOH, R₂ is a peptide radical selected from thegroup consisting of peptide hormones, growth factors, cytokines,neurotransmitters, neuropeptides, antibody fragments, cyclosporines andcoagulation factors as well as derivatives and fragments thereof, orrepresents —NH—CHR₅—COOH wherein R₅ is selected from the groupconsisting of the side chains of Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr,Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl,Orn, Sar and Me-Gly.

[0025] The term “side chain of a natural or synthetic amino acid” meansthe radicals of each natural or synthetic amino acid positioned on theα-carbon atom. The amino acid radicals R₁ and R₂ may be present in theD- and the L-configuration, the natural L-configuration being preferred.Below, the customary abbreviations and designations in the 3-letter codeare used to characterise the amino acids.

[0026] According to one embodiment, especially compounds of the formula(I) are used and claimed, respectively, wherein R₁ represents—NH—CHR₄—COOH and R₂ represents —NH—CHR₅—COOH wherein R₄ and R₅ may bethe same or different and are as defined above. More preferably, R₄ andR₅ are independently selected from the group consisting of the sidechains of Ala, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp,Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.

[0027] According to another embodiment, compounds of the formula (I) areused or claimed, respectively, wherein R₁ represents —OR₃ and R₂represents an L-amino acid radical —NH—CHR₅—COOH, wherein R₅ is selectedfrom the group consisting of the side chains of Ala, Val, Leu, Trp, Phe,Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, Citrullin, Hcy,Hse, Hyp, Hyl, Orn, Sar and Me-Gly.

[0028] Especially preferably R₅ is a polar amino acid in bothembodiments, even more preferably a charge-bearing amino acid selectedfrom the group consisting of asparagine, glutamine, lysine, arginine andhistidine.

[0029] When the radical R₁ represents —OR₃, i.e. when the compound ofthe formula (I) to be used according to the invention or claimed,respectively, is a monoamido fumaric acid monoester or monoamide, R₃ ispreferably selected from the group consisting of a linear, branched,cyclic, saturated or unsaturated C₁₋₂₄ alkyl radical, preferably a C₁₋₆alkyl radical, a phenyl radical or a C₆₋₁₀ aralkyl radical and thisradical is optionally substituted with halogen (F, Cl, Br, I), hydroxy,C₁₋₄ alkoxy, nitro or cyano. Preferably R₃ is methyl, ethyl, n-propyl,isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl,2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl,allyl, 2-hydroxyethyl, 2- or 3-hydroxypropyl, 2,3-dihydroxypropyl,2-methoxyethyl, methoxymethyl or 2- or 3-methoxypropyl. Most preferablyR₃ is methyl or ethyl.

[0030] According to another embodiment of the invention, compounds ofthe formula (I) are used wherein R₁ represents —OR₃, preferably withR₃=methyl or ethyl, and R₂ represents a peptide radical with 2 to 100,preferably 2 to 30 amino and most preferably 5 to 25 amino acids bondedvia an amide bond. Said peptide radical may be a natural, recombinant orsynthetic peptide radical.

[0031] More preferably, the peptide radical R₂ is selected from thegroup consisting of peptide hormones, growth factors, cytokines,neurotransmitters, neuropeptides, antibody fragments, coagulationfactors and cyclosporines as well as derivatives and fragments thereof.Said peptides may be purified from natural sources, recovered byrecombinant methods or synthesised in accordance with known processes.The use of synthetic peptides is preferred.

[0032] Coupling the fumaric acid body to such a functional peptide hasthe advantage of the peptide providing a transmission of the activeingredient “fumaric acid body” to target cells with which the peptideportion of the amides of the invention interacts. At the same time, thepeptide portion may have its own effect on the disease to be treated sothat a combination therapy is effected in this case. However, acombination therapy and/or strategic administration permit reduction ofthe dose to be administered in a desirable, possibly even synergisticmanner.

[0033] According a preferred embodiment of the invention, the peptideradical may be a cyclosporine radical the cycle of which may be cleavedat each peptide bond in order to enter into the fumaric acid amidebonding. In general, all cyclosporines may be bonded to the fumaric acidbody by an amide bond in the invention. Since cyclosporines are cyclicpeptides, the peptide ring is generally cleaved at any position (at anyamide bond) in order to obtain a linearised cyclosporine capable ofentering into an amide bond. Preferably cyclosporine A linearised beforeposition 1 is used.

[0034] The term “peptide hormones” as used here means physiologicallyhighly active peptides with approximately up to 100 amino acids whichdevelop a hormone effect or hormone-like effect. Examples are theglandular peptide hormones of the pituitary gland such as corticotropin,follitropin, lutropin, melanotropin, prolactin, somatotropin,thyrotropin, oxytocin and vasopressin, the releasing hormones andinhibiting factors of the hypothalamus, the peptide hormones from thepancreas, stomach or intestine such as glucagon, insulin, somatostatin,sectretin, gastrin and cholecystokinin, the peptide hormones of thethyroid such as calcitonin, parathyrin and such like.

[0035] The term “growth factors” means hormone-like peptides andproteins which support cell division and cell differentiation, promotegrowth and organ development and are needed for wound healing. Examplesare colony-stimulating factors, the epidermal growth factor (EGF),erythropoietin, fibroblast growth factors, haematopoietic growthfactors, hepatocyte growth factors, insulin and insulin-like growthfactors, the platelet-derived growth factor (PDGF), thrombopoietin,transforming growth factors, viral growth factors, but the interleukins,too.

[0036] The term “cytokines” as used in the present application refers topolypeptides which are secreted by cells and, after bonding withspecific receptors, may influence the function of other, usuallyadjacent cells. Cytokines primarily regulate the complex interaction ofthe cells of the immune system. Examples of such cytokines areinterferons, interleukins, chemokines or colony-stimulating factors.

[0037] The term “neurotransmitter” means messenger substances whicheffect the chemical signal or information transmission on the synapsesof the nervous system. Depending on their chemical characteristics,neurotransmitters are divided into amino acids such as glutamine acid,amino acid derivatives such as acetylcholine, monoamines like thecatechol amines, such as L-noradrenalin, L-adrenalin and dopamine,serotonin and peptides. Accordingly, the “neuropeptides” likebradykinin, but also the enkephalines, endorphin etc. are a sub-group ofthe neurotransmitters.

[0038] The term “coagulation factors” as used here means proteins of thecoagulation cascade. Likewise, the peptide which, in the invention, maybe coupled to the fumaric acid via an amide-bonding may be an antibodyfragment, said fragment preferably also comprising a recognitionsequence and/or bonding sequence.

[0039] Fragments and/or derivatives of all the peptides enumerated abovewhich are suitable for the invention may also be used. The term“fragment” means a portion of the above-mentioned peptides which iscapable of amide bonding. Preferably, said fragment comprisesrecognition sequences for arranging bonding to a cell receptor and/or anactive centre for transmitting an active function.

[0040] The term “derivative” means a peptide which may be derived fromthe above-mentioned peptides and/or fragments by homologoussubstitution, deletion or insertion of one or more amino acid(s) into orfrom the peptide chains.

[0041] The fumaric acid amides of the invention may be prepared inaccordance with the above-mentioned U.S. patents to Blank.

[0042] In a third aspect, the present invention relates to drugscomprising a fumaric acid amide as defined above or mixtures thereof.The drugs obtained through the use according to the invention and/orthrough the use of the claimed fumaric acid amides may be present informs suitable for oral, nasal, parenteral, rectal, pulmonal, ophthal ortransdermal administration.

[0043] Preferably, the drug is intended for oral administration and ispresent in the form of tablets, coated tablets, capsules, granulate,solutions for drinking, liposomes, nano-capsules, micro-capsules,micro-tablets, pellets or powders as well as granulate, micro-tablets,pellets and powder filled in capsules, micro-tablets filled in capsulesand powder filled in capsules.

[0044] According to a particularly preferred embodiment, the drug is asolid oral dosage form and, even more preferably, has an enteric coating(coating resistant to gastric acid). For example such a coating may beprovided on tablets, coated tablets, micro-tablets, pellets or capsules.

[0045] As a matter of principle, the drug of the invention may containsuitable pharmaceutically acceptable carriers, excipients, additivesetc. These are known to the person skilled in the art and do not requirean explanation.

[0046] The use of micro-tablets or pellets is most preferred.Preferably, these have a mean diameter of 300 to 5000 μm, morepreferably 300 to 2000 μm, when uncoated.

[0047] When administered parenterally by injection, the composition ispresent in a form suitable for this purpose. All customary liquidcarriers suitable for injection may be used.

[0048] In any case, it is preferred that a single dose of the drugcontains an amount of the fumaric acid amide of the formula (I) whichcorresponds or is equivalent to an amount of 1 to 500 mg, preferably 10to 300 mg and most preferably 10 to 200 mg of fumaric acid.

1. The use of fumaric acid amides of the general formula (I)

wherein R₁ represents OR₃ or a D- or L-amino acid radical —NH—CHR₄—COOHbonded via an amide bond, wherein R₃ is hydrogen, a straight-chained orbranched, optionally substituted C₁₋₂₄ alkyl radical, a phenyl radicalor C₆₋₁₀ aralkyl radical and R₄ is a side chain of a natural orsynthetic amino acid and R₂ represents a D- or L-amino acid radical—NH—CHR₅—COOH bonded via an amide bond or a peptide radical comprising 2to 100 amino acids bonded via an amide bond, wherein R₅ is a side chainof a natural or synthetic amino acid, for preparing a drug (1) for thetherapy of an autoimmune disease selected from the group consisting ofpolyarthritis, multiple sclerosis, graft-versus-host reactions,juvenile-onset diabetes, Hashimoto's thyroiditis, Grave's disease,systemic Lupus erythematodes (SLE), Sjogren's syndrome, perniciousanaemia and chronic active (=lupoid) hepatitis; (2) for use intransplantation medicine; (3) for the therapy of mitochondrial diseasesselected from the group consisting of Parkinson syndrome, Alzheimer'sdisease, Chorea Huntington disease, retinopathia pigmentosa or forms ofmitochondrial encephalomyopathy; as well as (4) for the therapy ofNF-kappaB mediated diseases selected from the group consisting ofprogressive systemic sclerodermia, osteochondritis syphilitica(Wegener's disease), cutis marmorata (livedo reticularis), Behcetdisease, panarteriitis, colitis ulcerosa, vasculitis, osteoarthritis,gout, arteriosclerosis, Reiter's disease, pulmonary granulomatosis,types of encephalitis, endotoxic shock (septic-toxic shock), sepsis,pneumonia, encephalomyelitis, anorexia nervosa, hepatitis (acutehepatitis, chronic hepatitis, toxic hepatitis, alcohol-inducedhepatitis, viral hepatitis, jaundice, liver insufficiency andcytomegaloviral hepatitis), Rennert T-lymphomatosis, mesangialnephritis, post-angioplastic restenosis, reperfusion syndrome,cytomegaloviral retinopathy, adenoviral diseases such as adenoviralcolds, adenoviral pharyngoconjunctival fever and adenoviral ophthalmia,AIDS, Guillain-Barré syndrome, post-herpetic or post-zoster neuralgia,inflammatory demyelinising polyneuropathy, mononeuropathia multiplex,mucoviscidosis, Bechterew's disease, Barett oesophagus, EBV(Epstein-Barr virus) infection, cardiac remodeling, interstitialcystitis, diabetes mellitus type II, human tumour radiosensitisation,multi-resistance of malignant cells to chemotherapeutic agents(multidrug resistance in chemotherapy), granuloma annulare and cancerssuch as mamma carcinoma, colon carcinoma, melanoma, primary liver cellcarcinoma, adenocarcinoma, kaposi's sarcoma, prostate carcinoma,leukaemia such as acute myeloid leukaemia, multiple myeloma(plasmocytoma), Burkitt lymphoma and Castleman tumour.
 2. The useaccording to claim 1 where R₁ represents an L-amino acid radical—NH—CHR₄—COOH and R₂ represents an L-amino acid radical —NH—CHR₅—COOH,wherein R₄ and R₅ may be the same or different and are as defined inclaim
 1. 3. The use according to claim 2 where R₄ and R₅ areindependently selected from the group consisting of the side chains ofAla, Val, Leu, Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys,Arg, His, Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.
 4. The useaccording to claim 1 where R₁ represents —OR₃ and R₂ represents anL-amino acid radical —NH—CHR₅—COOH, wherein R₅ is selected from thegroup consisting of side chains of Ala, Val, Leu, Trp, Phe, Met, Tyr,Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse, Hyp,Hyl, Orn, Sar and Me-Gly.
 5. The use according to claim 1 where R₁represents —OR₃ and R₂ represents a peptide radical with 2 to 30 aminoacids bonded via an amide bond.
 6. The use according to claim 1 or 5where the peptide radical R₂ is selected from the group consisting ofpeptide hormones, growth factors, cytokines, neurotransmitters,neuropeptides, antibody fragments, coagulation factors and cyclosporinesas well as derivatives and fragments thereof.
 7. The use according toclaim 6 where the peptide radical is a cyclosporine radical the cycle ofwhich may be cleaved at each peptide bond so as to enter into thefumaric acid amide bond.
 8. The use according to claim 7 wherecyclosporine A linearised before position 1 is used.
 9. The useaccording to any of the claims 1 to 8 where R₃ represents a linear,branched, cyclic, saturated or unsaturated C₁₋₂₄ alkyl radical, a phenylradical or a C₆₋₁₀ aralkyl radical and this radical is optionallysubstituted with halogen (F, Cl, Br, I), hydroxy, C₁₋₄ alkoxy, nitro orcyano; preferably R₃ is methyl, ethyl, n-propyl, isopropyl, n-butyl,sec-butyl, t-butyl, pentyl, cyclopentyl, 2-ethylhexyl, hexyl,cyclohexyl, heptyl, cycloheptyl, octyl, vinyl, allyl, 2-hydroxyethyl, 2-or 3-hydroxypropyl, 2,3-dihydroxypropyl, 2-methoxyethyl, methoxymethylor 2- or 3-methoxypropyl.
 10. The use according to claim 9where R₃ ismethyl or ethyl.
 11. The use according to claim 1 where the drug ispresent in a form suitable for oral, nasal, parenteral, rectal,pulmonal, ophthal or transdermal administration.
 12. The use accordingto claim 1 where the drug is intended for oral administration and ispresent in the form of tablets, coated tablets, capsules, granulate,solutions for drinking, liposomes, nano-capsules, microcapsules,micro-tablets, pellets or powders as well as granulate, microtablets,pellets and powder filled in capsules.
 13. The use according to claim 12where the drug is a solid oral dosage form and has an enteric coating(coating resistant to gastric acid).
 14. The use according to claim 12where the micro-tablets or pellets without coating have a mean diameterof 300 to 5000 μm, preferably 300 to 2000 μm.
 15. The use according toany of the claims 1 to 14 where the drug contains an amount of thefumaric acid amide of formula (I) per single dose which corresponds to 1to 500 mg, preferably 10 to 300 mg of fumaric acid.
 16. A fumaric acidamide of the formula (I)

wherein R₁ represents OR₃ or a D- or L-amino acid radical —NH—CHR₄—COOHbonded via an amide bond, wherein R₃ is hydrogen, a straight-chained orbranched, optionally substituted C₁₋₂₄ alkyl radical, a phenyl radicalor C₆₋₁₀ aralkyl radical and R₄ is a side chain of a natural orsynthetic amino acid and R₂ represents a D- or L-amino acid radical—NH—CHR₅—COOH bonded via an amide bond or a peptide radical comprising 2to 100 amino acids bonded via an amide bond, wherein R₅ is a side chainof a natural or synthetic amino acid, with the proviso that when R₃═H,R₂ is a peptide radical selected from the group consisting of peptidehormones, growth factors, cytokines, neurotransmitters, neuropeptides,antibody fragments, coagulation factors and cyclosporines as well asderivatives and fragments thereof; and when R₁═—NH—CHR₄—COOH, R₂ is apeptide radical selected from the group consisting of peptide hormones,growth factors, cytokines, neurotransmitters, neuropeptides, antibodyfragments, cyclospolines and coagulation factors as well as derivativesand fragments thereof, or represents —NH—CHR₅—COOH wherein R₅ isselected from the group consisting of the side chains of Ala, Val, Leu,Trp, Phe, Met, Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His,Citrullin, Hcy, Hse, Hyp, Hyl, Orn, Sar and Me-Gly.
 17. A fumaric acidamide according to claim 16 wherein R₁ represents —OR₃ and R₂ representsan L-amino acid radical —NH—CHR₅—COOH wherein R₅ is selected from thegroup consisting of the side chains of Ala, Val, Leu, Trp, Phe, Met,Tyr, Thr, Cys, Asn, Gln, Asp, Glu, Lys, Arg, His, Citrullin, Hcy, Hse,Hyp, Hyl, Orn, Sar and Me-Gly.
 18. A fumaric acid amide according toclaim 16, wherein R₁ represents —OR₃ and R₂ represents an peptideradical with 2 to 30 amino acids bonded via an amide bond.
 19. A fumaricacid amide according to claim 16 or 18 wherein the peptide radical R₂ isselected from the group consisting of peptide hormones, growth factors,cytokines, neurotransmitters, neuropeptides, antibody fragments,cyclosporines and coagulation factors as well as derivatives andfragments thereof.
 20. A fumaric acid amide according to claim 19wherein the peptide radical is a cyclosporine radical the cycle of whichmay be cleaved at each peptide bond in order to enter into the fumaricacid amide bonding.
 21. A fumaric acid amide according to claim 20wherein cyclosporine A linearised before position 1 is used.
 22. Afumaric acid amide according to any of the claims 16 to 21 wherein R₃represents a linear, branched, cyclic, saturated or unsaturated C₁₋₂₄alkyl radical, a phenyl radical or a C₆₋₁₀ aralkyl radical and theseradicals are optionally substituted with halogen (F, Cl, Br, I),hydroxy, C₁₋₄ alkoxy, nitro or cyano; preferably R₃ is methyl, ethyl,n-propyl, isopropyl, n-butyl, sec-butyl, t-butyl, pentyl, cyclopentyl,2-ethylhexyl, hexyl, cyclohexyl, heptyl, cycloheptyl, octyl, vinyl,allyl, 2-hydroxyethyl, 2- or 3-hydroxypropyl, 2-methoxyethyl,2,3-dihydroxypropyl, methoxymethyl or 2- or 3-methoxypropyl.
 23. Afumaric acid amide according to claim 22 wherein R₃ is methyl or ethyl.24. A drug comprising a fumaric acid amide according to any of theclaims 16 to
 23. 25. A drug according to claim 24, said drug beingpresent in a form suitable for oral, nasal, parenteral, rectal,pulmonal, ophthal or transdermal administration.
 26. A drug according toclaim 24, said drug being intended for oral administration and beingpresent in the form of tablets, coated tablets, capsules, granulate,solutions for drinking, liposomes, nano-capsules, microcapsules,micro-tablets, pellets or powders as well as granulate, microtablets,pellets and powder filled in capsules.
 27. A drug according to claim 26,said drug being a solid oral dosage form and having an enteric coating(coating resistant to gastric acid).
 28. A drug according to claim 26,wherein the micro-tablets or pellets without coating have a meandiameter of 300 to 5000 μm, preferably 300 to 2000 μm.
 29. A drugaccording to any of the claims 24 to 28, said drug containing an amountof the fumaric acid amide of formula (I) per single dose whichcorresponds to 1 to 500 mg, preferably 10 to 300 mg of fumaric acid.